Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter
Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter
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甜菜碱补充剂通过减少过氧化物酶体增殖物激活受体α启动子的甲基化来减轻载脂蛋白E缺陷小鼠的肝脏甘油三酯积累
DOI：
10.1186/1476-511x-12-34
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发表时间：
2013-03-13
影响因子：
4.5
通讯作者：
Zhu, Huilian
中科院分区：
文献类型：
--
作者：
Wang, Lijun;Chen, Li;Zhu, Huilian
甜菜碱是一种甲基供体，被认为是一种增脂物质。但其机制尚不清楚。肝脂肪变性与参与肝脂质代谢的基因异常表达有关。DNA甲基化有助于基因表达的失调。在这里，我们假设甜菜碱的补充和随后的DNA甲基化修饰改变了参与肝脏脂质代谢的基因的表达，从而减轻了肝脏甘油三酯的积累。方法野生型（WT） C57BL/6小鼠（n= 6）饲喂AIN-93 G饲粮。将与WT小鼠体重匹配的ApoE−/−小鼠（n= 12）分为两组（每组6只），分别饲喂AIN-93 G饲粮和AIN-93 G饲粮中添加2%甜菜碱/100 G饲粮。干预七周后，小鼠被处死。采用高效液相色谱法测定肝脏甜菜碱、胆碱、同型半胱氨酸浓度。用紫外分光光度法测定肝脏氧化剂活性和甘油三酯水平。最后，检测肝脏cppar α基因及其靶基因的表达水平和ppar α基因的甲基化状态。结果与WT小鼠相比，apoe−/−小鼠肝脏甘油三酯升高，GSH-Px活性降低。甜菜碱干预逆转甘油三酯沉积，增强肝脏SOD和GSH-Px活性。有趣的是，与没有甜菜碱干预的WT小鼠和apoe−/−小鼠相比，添加甜菜碱的小鼠肝脏胆碱浓度显著增加，甜菜碱和同型半胱氨酸浓度显著降低。在apoe−/−小鼠中，ppar α和cpt1的表达降低，而offas的表达明显升高。同时，PPAR α启动子甲基化水平在apoe−/−小鼠中略有升高，但无显著性。补充甜菜碱可上调ppar α及其靶基因（CPT1、CYP2E1）的表达，逆转apoe−/−小鼠ppar α启动子的高甲基化。PPAR α甲基化与肝甜菜碱浓度呈正相关。结论补充甜菜碱可通过降低ppar α启动子甲基化和上调ppar α及其靶基因mRNA表达，减轻肝脏甘油三酯积累，提高抗氧化能力。
BackgroundBetaine is a methyl donor and has been considered as a lipotropic effect substance. But its mechanism remains unclear. Hepatic steatosis is associated with abnormal expression of genes involved in hepatic lipid metabolism. DNA methylation contributes to the disregulation of gene expression. Here we hypothesized that betaine supplement and subsequent DNA methylation modifications alter the expression of genes that are involved in hepatic lipid metabolism and hence alleviate hepatic triglyceride accumulation.MethodsMale wild-type (WT) C57BL/6 mice (n= 6) were fed with the AIN-93 G diet.ApoE−/−mice (n = 12), weight-matched with the WT mice, were divided into two groups (n= 6 per group), and fed with the AIN-93 G diet and AIN-93 G supplemented with 2% betaine/100 g diet. Seven weeks after the intervention, mice were sacrificed. Liver betaine, choline, homocysteine concentration were measured by HPLC. Liver oxidants activity and triglyceride level were assessed by ultraviolet spectrophotometry. Finally, hepaticPPAR alphagene and its target genes expression levels and the methylation status of thePPAR alphagene were determined.ResultsApoE−/−mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and theApoE−/−mice absent with betaine intervention. Expression ofPPAR alphaandCPT1were decreased and expression ofFASwas markedly increased inApoE−/−mice. In parallel,PPAR alphapromoter methylation level were slightly increased inApoE−/−mice though without significance. Betaine supplement upregulated expression ofPPAR alphaand its target genes (CPT1,CYP2E1) and reversed hypermethylation ofPPAR alphapromoter ofApoE−/−mice. Furthermore,PPAR alphamethylation was positively correlated with hepatic betaine concentration.ConclusionsOur findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasingPPAR alphapromoter methylation and upregulatingPPAR alphaand its target genes mRNA expression.